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Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's dementia
Open accessAbstract
Fluorodeoxyglucose positron emission tomography (PET) studies have found that patients with Alzheimer's dementia (AD) have abnormally low rates of cerebral glucose metabolism in posterior cingulate, parietal, temporal, and prefrontal cortex. We previously found that cognitively normal, late-middle-aged carriers of the apolipoprotein E ε4 allele, a common susceptibility gene for late-onset Alzheimer's dementia, have abnormally low rates of glucose metabolism in the same brain regions as patients with probable AD. We now consider whether ε4 carriers have these regional brain abnormalities as relatively young adults. Apolipoprotein E genotypes were established in normal volunteers 20–39 years of age. Clinical ratings, neuropsychological tests, magnetic resonance imaging, and PET were performed in 12 ε4 heterozygotes, all with the ε3/ε4 genotype, and 15 noncarriers of the ε4 allele, 12 of whom were individually matched for sex, age, and educational level. An automated algorithm was used to generate an aggregate surface-projection map that compared regional PET measurements in the two groups. The young adult ε4 carriers and noncarriers did not differ significantly in their sex, age, educational level, clinical ratings, or neuropsychological test scores. Like previously studied patients with probable AD and late-middle-aged ε4 carriers, the young ε4 carriers had abnormally low rates of glucose metabolism bilaterally in the posterior cingulate, parietal, temporal, and prefrontal cortex. Carriers of a common Alzheimer's susceptibility gene have functional brain abnormalities in young adulthood, several decades before the possible onset of dementia.
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“PET studies have also revealed that human carriers of the APOE ε4 allele experience reduced brain glucose metabolism at a young age (20–39 years old) [18].”
From APOE4 genotype exacerbates the depression-like behavior of mice during aging through ATP decline (2021) · cites this paper as [18]
In the citing paper
“As shown in previous studies, the brains of APOE4 carriers display decreased glucose utilization in numerous AD-relevant brain regions, as observed by FDG-PET16–18.”
From APOE4 is Associated with Differential Regional Vulnerability to Bioenergetic Deficits in Aged APOE Mice (2020) · cites this paper as [17]
In the citing paper
“early reports by Reiman and colleagues demonstrated that both young and old APOE4 carriers display decreased glucose utilization, as measured by fluorodeoxyglucose positron emission tomography (FDG-PET), in brain regions similar to those seen with AD patients16–18.”
From APOE4 is Associated with Differential Regional Vulnerability to Bioenergetic Deficits in Aged APOE Mice (2020) · cites this paper as [17]
In the citing paper
“Cognitively normal individuals at risk for AD, including those carrying ApoE4, showed reduced cerebral metabolism of glucose (Reiman et al., 2004(Reiman et al., , 2005)).”
From Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention (2018) · cites this paper as Reiman et al., 2004
In the citing paper
“One of the major changes that typically occurs in the preclinical AD brain is the perturbed brain energy metabolism.”
From Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention (2018) · cites this paper as Reiman et al., 2004
In the citing paper
“Young, cognitively normal apoE4 carriers have glucose hypometabolism in brain regions affected by AD [29–31]”
From Neuronal Apolipoprotein E4 Expression Results in Proteome-Wide Alterations and Compromises Bioenergetic Capacity by Disrupting Mitochondrial Function (2019) · cites this paper as [31]
In the citing paper
“Furthermore, functional brain imaging shows reduced resting brain activity in subjects with AD, and even in genetically at-risk subjects decades prior to predicted cognitive symptoms [150].”
From Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease (2010) · cites this paper as [150]
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Metadata
- Authors
- Reiman, E. M., Chen, K., Alexander, G. E., Caselli, R. J., Bandy, D., Osborne, D., Saunders, A. M., & Hardy, J.
- Affiliations
- Mayo Clinic (US)
- Translational Genomics Research Institute (US)
- National Institutes of Health (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2003-12-19
- Volume
- 101
- Issue
- 1
- Pages
- 284-289
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC314177
- OpenAlex
- W1986144956
- Semantic Scholar
- eb994dc7b585b491e0b2814b9c41734a99570732
- Cited by
- 977
- References
- 71
- Citations by year
- 2026: 19 · 2025: 19 · 2024: 29 · 2023: 27 · 2022: 37 · 2021: 42 · 2020: 45 · 2019: 47 · 2018: 41 · 2017: 43 · 2016: 40 · 2015: 40 · 2014: 55 · 2013: 55 · 2012: 65
- FWCI
- 21.42
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- National Institute on Aging (P30 AG19610-02, P30AG019610)
- National Institute of Mental Health (R01 MH57899-01, R01MH057899)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Cognitive Abilities and Testing
- Keywords
- Alzheimer's disease, APOE ε4, genetic risk, brain glucose metabolism, brain abnormalities, young adults, posterior cingulate cortex, prefrontal cortex, parietal cortex, temporal cortex
- MeSH terms
- Adult, Alleles, Alzheimer Disease, Apolipoproteins E, Brain, Female, Glucose, Heterozygote, Humans, Male, Risk Factors, Tomography, Emission-Computed, Case-Control Studies, Apolipoprotein E3, Apolipoprotein E4
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